Antidepressant composition and method of using same



United States Patent Ofi" 3,225,294 Patented Dec. 28, 1965 3,226,294 ANTIDEPRESSANT COMPOSITIDN AND METHOD (BF USING SAME Carl E. Nelson, Lansdale, Pa., assignor to Merck & Co. Inc, Railway, N..l., a corporation of New Jersey No Drawing. Filed Apr. 30, 1963, Ser. No. 277,019 7 Claims. (Cl. 167-55) This invention relates to pharmaceutical compositions and methods. More particularly, this invention relates to compositions having antidepressant actions with minimum cardio-vascular side efiects, and to methods for administering such compositions.

Compounds of the class of amitriptyline, -(3-rnethylaminopropyl)-SH-dibenzo[a,d]cycloheptene, and their congeners are well known psychotherapeutic agents exhibiting, among a wide variety of pharmacological actions, powerful antidepressant and tranquilizing modalities. These compounds, however, while successfully inducing tranquilization, also have a powerful sedative effect which is frequently undesirable in ambulatory patients. Imipramine, however, exhibits antidepressant activity without a tranquilizing component.

The amphetamines, on the other hand, are a well known class of sympathomimetic agents employed mainly as stimulants of the central nervous system in the treatment of a variety of nervous disorders such as narcolepsy, alcoholism, mental depression, post-encephalitic parkinsonism, fatigue and the like. Normal dosages of the amphetamines, however, have a potent stimulatory action on the central nervous system which frequently gives rise to a number of undesirable side effects. For example, cortical stimulation by the amphetamines at a single dose of 5 mg. to mg, administered orally, frequently causes such undesirable side effects as tremors,

restlessness, increased motor activity, insomia and peripheral (vaso-pressor) cardio-vascular effects which give rise to an abnormal and undesirable increase in both systolic and diastolic blood pressure.

Accordingly, it is an object of this invention to coadminister psychotherapeutic agents of the class of amitriptyline, 5-(3-methylaminopropyl) 5H dibenzo[a,d] cycloheptene, and imipramine and their congeners with sympathomimetic amines such as the amphetamine in a manner to block the cardio-vascular side effects of the amphetamines. In the case of amitriptyline, a further object is to block the sedative effect of this drug by coadministering it with an amphetamine, while concurrently blocking the aforementioned cardio-vascular side effect.

The foregoing and other objects are accomplished in accordance with the method of the present invention by providing a therapeutically active pharmaceutical composition which includes active constituents which coact in the treatment of mental and nervous disorders. The composition described herein includes, as active ingredients, a compound of the amitriptyline class in combination with a subclinical dose of a sympathomimetic amine. It is important that the dosage of the sympathomimetic amine, combined in accordance with the invention, be drastically less than its normal dosage when administered alone.

The amphetamines are also characterized by their utility in the field of anti-obesity as anorexigenic agents. However, the same side effects are observed, namely, cardio-vascular side effects and central nervous system side effects, the latter leading to nervousness, tremor, insomnia, etc. Accordingly, it is another object to provide agents for co-administration with the amphetamines for this purpose which block out the aforementioned side effects.

Compounds of the amitriptyline group are known in the art and are distinguished by having a common pharmacologic action and similar chemical structure.

Amitriptyline itself is 5-(3-dimethylaminopropylidine)- dibenzyl[a,d][l,4]cycloheptadiene. its preparation is described in Example 1 of British Patent No. 858,187, published January 11, 1961.

Imipramine is 5-(Z-dimethyl-aminopropyl)-10,1l-dihydro-5H-dibenz[b,f]azepine hydrochloride. It has the structural formula:

Imipramine is used medically as an anti-depressant and tranquilizer; its recommended doses (oral) are mg. per day, the maximum dosage not to exceed about 250 mg. per day. It has been established that average or large doses may cause xerostomia, blurring of vision, tachycardia, dizziness, paresthesias and other symptoms.

5 (S-methylaminopropyl)-5H-dibenzo]a,d]cycloheptene may be prepared from 5-(3-dimethylaminopropyl)- 5H-dibenzo[a,d] cycloheptene by adding benzene dropwise in a stirred solution of cyanogen bromide in benzene. Some heat is evolved. The mixture is stirred for 3 hours at room temperature, and filtered to remove any precipitate which forms. The filtrate, together with a benzene wash of the precipitate, is evaporated to dryness on a steam-bath under reduced pressure to remove excess cyanogen bromide and solvent. The residual crude cyanamide is dissolved in benzene, and the solution is washed with dilute hydrochloric acid to remove any unchanged amine, then with water. The benzene solution is then evaporated under reduced pressure leaving 5-(3-N-cyano' aminopropyl)-5H-dibenzo[a,d]cycloheptene as a yellow oil weighing typically 19.6 g. Under hydrolysis, there is obtained 5- 3-methylaminopropyl -5H-dibenzo [a,d] cycloheptene. This may be converted to its hydrochloride salt directly by treatment with ethanolic hydrogen chloride. After recrystallization from a mixture of isopropyl alcohol and ether, the hydrochloride salt melts at 166.5- 167.5 C. (uncorrected).

The sympathomimetic amines used prophylactically in the compositions of the present invention belong to the class known as amphetamines and include d-amphetamine, amphetamine phosphate, amphetamine sulfate and methamphetamine.

d-Amphetamine is l-phenyl-Z-amino propane and has the following chemical formula:

Q-omonom NHCH The composition of the present invention combines as ingredients compounds of the amitriptyline class with a sympathomimetic amine and, in unitary form, the composition is effective in the treatment of mental. illness, while prophylactically antagonizing the sedative effect commonly associated with the amitriptyline type of drugs. Furabout 75 to 250 mg. per day, dictated by the patients need for the tranquilizer.

EXAMPLE 2 tually complementary in their relationship and pharma- 5 Following the procedure described in Example 1 and cologic action. It is of importance to observe that amiusing 75 mg. of imipramine in place of 25 or 50 mg. of triptyline exerts a transient sedative effect in man with an th m mat rial in the formulation of Example 1, there approximate 'g of aboutfitwo Weeks Y- Simiiafare produced similarly effective compositions. ly, tolerance to t e pressor e ects of amphetamine becomes operative within the same time span. It will be EXAMPLE 3 apparent, therefore, that co-administration of amitripty- The following tables illustrate combinations of agents line and an amphetamine is critical primarily during the according to this invention in milligrams: initial phase of therapy.

For effective prophylaxis of the sedative effect, a sub- Table 3(a) clinical dosage of the sympathomimetic amine is prefer- The following table shows dosages of imipramine comably employed for the great majority of patients. Thus bined with any Single one of the sympathomimetic amines for irnipramine (75 mg. to 250 mg. per day) the daily listed, giving the amounts of each in miligrams per dose, dosage of d-amphetamine ranges from about 0.05 mg. to to be administered three times per day.

Imipramine d-Amphetamine 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.5 5.0 Amphetamine phosphate. 0.5 1.0 1.5 2.0 2.5 3.0 4.0 4.5 5.0 Amphetamine sulfate 0.5 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 Methamphetamine 0.5 1.0 2.0 2.5 3.0 3.5 4.0 4.5 2.5

5 mg. per day, the preferred range being about 0.5 mg. to 25 Table 3(1)) 5 mg. per day, with no evidence of either sedative or excitatory effects. The usual therapeutic dosage of arnphet- The following table is similar to Table 3 (a) in that it is amine is 5 mg. to 20 mg. per dose. When chronic medinot intended to show combinations of more than two cation is employed, the usual dose is 5 mg. to 10 mg. reagents, but shows amitriptyline combined in usable tabpeated three or four times daily. 20 lets with any one of the sympathomimetic amines listed,

In the actual formulation of a tablet containing the amiquantities being given in milligrams per dose, admintriptyline type drug with the sympathomimetic amine, it is istered three times per day.

Amitriptyline 25 40 50 05 75 100 125 140 150 d-Amphetamine 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.5 5.0 Amphetamine phosphate" 0.5 1.0 1.5 2.0 2.5 3.0 4.0 4.5 5.0 Amphetamine sulfate 0.5 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 Methamphetamine 0.5 1.0 2.0 2.5 3.0 3.5 4.0 4.5 2.5

necessary in the great majority of cases that only a sub- Table 3 clinical dose of the latter be used. Generally only about 40 0.5 mg. to 2.0 mg. of the sympathomimetic amine need be The iOiiOWiiig iabie is Simiiaf Tabies 3 and incorporated into a dose of between 25 mg. and 50 mg. of and ShOWS y p py 7 the amitriptyline type material in order to achieve the cycioileptene Combined in usable tablet form With y desired result. one of the sympathomimetic amines listed, quantities be- The following are examples further illustrating the in- 45 g given in milligrams P dose, administered three tiims vention per day.

heptene 5 5 5 10 10 10 15 15 15 d-Amphetamiue 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.5 5.0

Amphetamine phosphate" 0.5 1.0 1.5 2.0 2.5 3.0 4.0 4.5 5.0

Amphetamine sulfate 0.5 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Methamphetamine 0.5 1.0 2.0 2.5 3.0 3.5 4.0 4.5 2.5

EXAMPLE 1 While the invention has been described with particu- 55 lar reference to a two-component system, it will be under- (A) (B) stood that a third component may be added, such as a member of the phenothiazine class as well as other agents,

p a emg 2 50 provided they do not inhibit the antagonistic action of g' f g fi 8- 5 8- 5 the sympathomimetic amine.

starch,EngfIIIIIIHM 21 21 60 Although this invention has been described specifically Magnesium steamieimg-fl 2 2 with reference to certain tranquilizing and sympathomi- The amitriptyline and d-amphetamine with 150 grams lactose and 21 grams of starch are mixed together. The blended powders are passed through a 40 mesh stainless steel screen to insure uniformity. The mix is wet granulated with 40 gm. of a 10% starch paste in water and sufficient water is added to make a suitable mass. The wetted materials then are screened through a #12 stainless steel screen and dried overnight at 40 C. Then the dried granules are screened though a #14 mesh screen; 2 gm. of magnesium stearate is added, blended and compressed into tablets weighing 200 mg. each. The tablets are sized with a protective coat of pharmaceutical glaze and sugar coated. They are administered in dosages of metic agents, it will be appreciated that many variations may be made without departing from the spirit and scope of this invention, including substituting equivalent elements and structure for those specifically illustrated and described, and even adding other ingredients which do not interfere with the complementary antagonistic actions. of the aforesaid tranquilizing and sympathomimetic agents.

Having thus described my invention, I claim:

1. A pharmaceutical composition having at least two components which complementarily antagonize an opposing pharmacologic tendency of the other comprising in prophylactic combination 25 mg. of 5-(3-dimethyl aminopropylidine)-dibenzyl[a,d] [1,41cycloheptadiene and 0.5.

mg. of l-phenyl-Z-amino propane and a non-toxic pharmaceutically acceptable carrier.

2. A method of treating depression while prophylactically antagonizing a sedative reaction comprising the oral administration to a patient of an antidepressant pharmaceutical composition comprising in combination 25 mg. to 150 mg. per day of 5-(3-dimethyl-aminopropylidine)-dibenzyl[a,d][1,4]cycloheptadiene and 1.5 mg. to mg. per day of l-phenyl-Z-aminopropane.

3. A method in accordance with claim 2 wherein said S-(B-dimethyl aminopropylidine dibenzyl[a,d] [1,4] cycloheptadiene is present in amounts of 25 mg. to 151) mg. per 0.5 mg. to 5 mg. of i-phenyl-Zaminopropane.

4. A pharmaceutical antidepressant composition consisting essentially of from about twenty-five to about two hundred and fifty parts by weight of S-(B-dimethylaminopropylidine)-51Ldibenzo(a,d)cycloheptene, and a subclinical quantity of from about five hundredths of one part to about five parts by weight of a sympathomimetic amine selected from the group consisting of l-phenyl-Z- aminopropane, l-phenyl-Z-aminopropane monophosphate, l-phenyl-2-aminopropane sulfate and 1-phenyl-2-methyl amino propane and a non-toxic pharmaceutically acceptable carrier. 5. A pharmaceutical antidepressant composition con sisting essentially of from about twenty-five to about two hundred and fifty parts by weight of 5-(3-dimethyl-aminopropylidine-dibenzyl (a,d) (1,4) cycloheptadiene, and a subclinical quantity of from about five hundredths of one part to about five parts by weight of a sympathomimetic amine selected from the group consisting of 1-phenyl-2- aminopropane, l-phenyl-Z-aminopropane monophosphate, l-phenyl-2-aminopropane sulfate and l-phenyl-Z-methyl aminopropane and a non-toxic pharmaceutically acceptable carrier.

6. A method of treating depression while prophylactically antagonizing a sedative reaction comprising the oral administration to a patient of an antidepressant pharmaceutical composition containing an efiective amount of a psychotherapeutic compound, 5-(3dimethylaminopropylidine)-dibenzyl(a,d)(1,4)cycloheptadiene and a sub-clinical amount of a sympathomimetic amine selected from the group consisting of l-phenyl-Z-aminopropane, l-phenyl- Z-aminopropane monophosphate, l-phenyl-Z-aminopropane sulfate and l-phenyl-Z-methyl aminopropane, said amine being present in an amount to antagonize prophylactically the sedative etiect of said psychotherapeutic compound notwithstanding the fact that the amount of said sympathomimetic amine administered is less than an amount Which would normally produce cardio-vascular and central nervous system stimulation.

7. A method of treating depression while prophylactically antagonizing a sedative reaction comprising the oral administration to a patient of an antidepressant pharmaceutical composition containing a psychotherapeutic compound, 5 (3-dimethylaminopropylidine)-5H-dibenzo(a, d)cycloheptene and a sub-clinical amount of a sympathomimetic amine selected from the group consisting of 1- phenyl-Z-aminopropane, l-phenyl-Z-aminopropane monophosphate, 1-phenyl-2-aminopropane sulfate and l-phenyl- Z-methyl aminopropane, said amine being present in an amount to antagonize prophylactically the sedative effect of said psychotherapeutic compound notwithstanding the fact that the amount of said sympathomimetic amine administered is less than an amount which would normally produce cardio-vascular and central nervous system stimulation.

References Cited by the Examiner Azirna: Am. I. of Psychiatry, vol. 115, No. 3, p. 245, September 1958.

Casey: The Am. I. of Psychiatry, vol. 117, No. 11, May 1961, p. 997.

Current Practice, British Med. Journal, No. 5324, January 19, 1963, p. 173.

Freed: The Am. J. of Psychiatry, vol. 117, No. 5, November 1960, p. 455.

Hare: British Med. J., No. 5270, January 6, 1962, p. 9. FDR: Physician Desk Reference, 1962, p. 836, Thora- Dex.

Physical Therapies: The American Handbook of Psychiatry, Pt. XI, page 1560, 1959.

JULIAN S. LEVITT, Primary Examiner.

FRANK CACCIAPAGLIA, JR., LEWIS GOTTS,

Examiners. 

1. A PHARMACEUTICAL COMPOSITION HAVING AT LEAST TWO COMPONENTS WHICH COMPLEMENTARILY ANTAGONIZE AN OPPOSING PHARMACOLOGIC TENDENCY OF THE OTHER COMPRISING IN PROPHYLACTIC COMBINATION 25 MG. OF 5-(3-DIMETHYL AMINOPROPYLIDINE)-DIBENZYL(A,D) (1,4)CYCLOHEPTADIENE AND 0.5 MG. OF 1-PHENYL-2-AMINO PROPANE AND A NON-TOXIC PHARMACEUTICALLY ACCEPTABLE CARRIER. 